title: Bisphosphonates modulate vital functions of human osteoblasts and affect their interactions with breast cancer cells.
abstract: Bisphosphonates (BPs) are in clinical use for the treatment of breast cancer patients with bone metastases. Their anti-resorptive effect is mainly explained by inhibition of osteoclast activity, but recent evidence also points to a direct action of BPs on bone-forming osteoblasts. However, the mechanisms how BPs influence osteoblasts and their interactions with breast cancer cells are still poorly characterized. Human osteoblasts isolated from bone specimens were characterized in depth by their expression of osteogenic marker genes. The influence of the nitrogen-containing BPs zoledronate (Zol), ibandronate (Iban), and pamidronate (Pam) on molecular and cellular functions of osteoblasts was assessed focusing on cell proliferation and viability, apoptosis, cytokine secretion, and osteogenic-associated genes. Furthermore, effects of BPs on osteoblast-breast tumor cell interactions were examined in an established in vitro model system. The BPs Zol and Pam inhibited cell viability of osteoblasts. This effect was mediated by an induction of caspase-dependent apoptosis in osteoblasts. By interfering with the mevalonate pathway, Zol also reduces the proliferation of osteoblasts. The expression of phenotypic markers of osteogenic differentiation was altered by Zol and Pam. In addition, both BPs strongly influenced the secretion of the chemokine CCL2 by osteoblasts. Breast cancer cells also responded to Zol and Pam with a reduced cell adhesion to osteoblast-derived extracellular matrix molecules and with a decreased migration in response to osteoblast-secreted factors. BPs revealed prominent effects on human osteoblasts. Zol and Pam as the most potent BPs affected not only the expression of osteogenic markers, osteoblast viability, and proliferation but also important osteoblast-tumor cell interactions. Changing the osteoblast metabolism by BPs modulates migration and adhesion of breast cancer cells as well.
authors.affiliation: Department of Gynecology and Obstetrics, University of Tübingen, Calwerstrasse 7, Tübingen, Germany. tatjana.kaiser@klinikum.uni-tuebingen.de
authors.forename: Tatjana
authors.initials: T
authors.lastname: Kaiser
authors.forename: Ingrid
authors.initials: I
authors.lastname: Teufel
authors.forename: Konstanze
authors.initials: K
authors.lastname: Geiger
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Vater
authors.forename: Wilhelm K
authors.initials: WK
authors.lastname: Aicher
authors.forename: Gerd
authors.initials: G
authors.lastname: Klein
authors.forename: Tanja
authors.initials: T
authors.lastname: Fehm
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics; D004164:Diphosphonates / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005819:Genetic Markers; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000077211:Zoledronic Acid
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018925:Chemokines; D004164:Diphosphonates; D005819:Genetic Markers; D007093:Imidazoles; D000077211:Zoledronic Acid; D020169:Caspases